Unique genetic variants of lean nonalcoholic fatty liver disease: a retrospective cohort study

Abstract

We investigated the prevalence and clinical metabolic characteristics of lean nonalcoholic fatty liver disease (NAFLD) in an elderly Chinese population and assessed the relevance of lipid markers and genetic variation. All 5,338 community subjects underwent detailed clinical and laboratory examinations and were divided into three groups: lean (Body mass index (BMI) < 23 kg/m2, n = 2,012), overweight (BMI = 23–24.9 kg/m2, n = 1,354), and obese (BMI ≥ 25 kg/m2, n = 1,972). Single nucleotide polymorphisms were selected based on those reported in previous NAFLD or obesity genome-wide association studies. The frequencies of alleles and genotypes were calculated and statistically analyzed with Pearson’s χ2 tests. One-way ANCOVA was used to test the association between positive SNPs and metabolic parameters in lean NAFLD individuals. Our results showed that the C allele frequency of rs2279026, the G allele of rs2279028, the C allele of rs780093, and the C allele frequency of rs1260326 were higher in obese NAFLD than in lean NAFLD (P < 0.05). In addition, we observed an association between the CC of rs1421085, TT of rs3751812, AA of rs8050136, and AA of rs9939609 genotypes in the FTO gene and low-density lipoprotein levels (P < 0.05). In conclusion, our findings provide a unique perspective on the prevalence, genetic characteristics, and metabolic profile of NAFLD in older lean individuals in China. This is the first study to examine the association between genetic variants in the FTO, TFAP2B and GCKR genes and NAFLD in a cohort of lean individuals.

Genetic and epigenetic determinants of non-alcoholic fatty liver disease (NAFLD) in lean individuals: a systematic review

“…A total of 18 studies were included in this review. The study sample sizes ranged from 53 participants ( 2 ) to 5,338 participants ( 3 ), with Li et al [2023] having the highest number of lean NAFLD patients included in their analysis (n=2,012). Studies were conducted globally, including Japan ( 4 , 5 ), Sri Lanka ( 6 ), Australia ( 7 ), India ( 8 ), Italy ( 9 ), and Sweden ( 10 ).…”

“…It is a prevalent liver disease worldwide, affecting approximately 25% of the general population and up to 75% of individuals with obesity and type 2 diabetes ( 1 , 2 ). The development of NAFLD is influenced by a complex interplay of genetic and environmental factors, including dietary habits and physical activity levels ( 3 - 5 ). NAFLD encompasses a spectrum of liver conditions, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which is characterized by liver inflammation, hepatocyte injury, and fibrosis ( 2 , 6 ).…”

What Is New in Metabolic Dysfunction-Associated Steatotic Liver Disease in Lean Individuals: From Bench to Bedside

“…Table 1 displays novel MASLD-associated genes and their corresponding SNPs in lean and non-lean individuals with or without MASLD. Most MASLD-associated genes are well documented to contribute to at least a part of lipid metabolism or iron homeostasis [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. In lean individuals, these genes comprise patatin-like phospholipase domain-containing 3 ( PNPLA3 ), transmembrane 6 superfamily member 2 ( TM6SF2 ), glucokinase regulatory protein ( GCKR ), TBC1 domain family member 1 ( TBC1D1 ), human homeostatic iron regulator ( HFE ), solute carrier family 17 member 3 ( SLC17A3 ), and fat mass and obesity-associated alpha-ketoglutarate dependent dioxygenase ( FTO ) [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”

“…One study of TBC1D1 (rs2279028; A/G) found that a low level of high-density lipoprotein (HDL) may be driven by either a homozygous A or G allele in an overdominant manner [ 32 ]. In addition, various intron variants of FTO (rs1421085, T/C; rs3751812, G/T; rs8050136, C/A; and rs9939609, T/A) may be attributed to an increase in the level of low-density lipoprotein (LDL) in a recessive manner [ 33 ]. Another interesting finding demonstrated that an increase in the C allele frequency of GCKR (rs1260326; T/C) was associated with a larger waist circumference (WC) in a dominant manner [ 31 ].…”

“…Most MASLD-associated genes are well documented to contribute to at least a part of lipid metabolism or iron homeostasis [23][24][25][26][27][28][29][30][31][32][33]. In lean individuals, these genes comprise patatin-like phospholipase domain-containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), glucokinase regulatory protein (GCKR), TBC1 domain family member 1 (TBC1D1), human homeostatic iron regulator (HFE), solute carrier family 17 member 3 (SLC17A3), and fat mass and obesity-associated alpha-ketoglutarate dependent dioxygenase (FTO) [23][24][25][26][27][28][29][30][31][32][33]. PNPLA3 and TM6SF2 are by far the most widely studied MASLD-associated genes in lean individuals.…”